The present invention relates to a process for producing 10-hydroxyanthracyclines stereospecifically from anthracyclines having no substituent at the 10-position thereof.
Specific examples of 10-hydroxyanthracyclines are betaclamycin (Journal of Antibiotics, 37, 935-938 (1984)) and 3'-deamino-3'-(4-morpholinyl)-13-deoxo-10-hydroxycarminomycin (hereinafter referred to as M-R20X2) (Japanese Patent Appln. No. 7196/1985). These are useful compounds which have antitumor activity. For example, betaclamycin inhibits proliferation of cultivated mouse leukemia cells (L1210) more effectively than aclacinomycin which has no substituent at the 10-position thereof. This betaclamycin has threfore drawn much attention. Furthermore, M-R20X2 also has remarkably high antitumor activity in comparison with 3'-deamino-3'-(4-morpholinyl)-13-deoxocarminomycin (hereinafter referred to as M-R20X) which differs from the M-R20X2 only in having no substituent (hydroxyl group) at the 10-position thereof. The comparative data will be shown hereinlater.
Accordingly, if an efficient method for introducing a hydroxyl group into the 10-position of an anthracycline having no substituent at the same position is developed, M-R20X can be readily converted into M-R20X2 which has higher antitumor activity while at the same time the antitumor activity of an anthracycline having no substituent at the 10-position thereof (e.g., adriamycin and daunomycin) can be expected to be enhanced by introducing a hydroxyl group into the same position.
The betaclamycin and M-R20X2 mentioned above, both having three asymmetric carbon atoms in the aglycon moiety thereof (7-, 9- and 10-position), are known to have the configurations 7S, 9R and 10R (Pharmazie, 39, 176-180(1984)).
Examples of organochemical approaches to the hydroxylation at 10-position include a process wherein a 9-10 epoxide is formed in an anthracyclinone having an olefin portion at the 9-10 position with the use of an organic peracid and the epoxide is subjected to ring cleavage to obtain a diastereomer mixture in a ratio of 9:1 (antidiol:syndiol) (A. S. Kende et al., J. Chem. Soc. Chem. Commun., 140 (1977)) and a process wherein a 10-ketoanthracycline is reduced to obtain a (10R) diastereomer and a (10S) diastereomer (the ratio of the (10R) diastereomer to the (10S) diastereomer obtained being 4:1) (H. Nakagawa et al., Tetradron Letters, 25, 31, 3355 (1984)).
The compounds obtained by these processes are mixtures of (10R) diastereomer and (10S) diastereomer and ordinarily have widely different antitumor activities. For this reason, these processes are accompanied by a problem in that the isomers except the desired compound which has the 7S, 9R and 10R configurations must be separated and removed. The former process further entails the problem of its inapplicability to glycosides.